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Zeitschrift Fur Rheumatologie Mar 2024
Topics: Humans; Anemia, Dyserythropoietic, Congenital; Immunologic Deficiency Syndromes; Interleukin-1; Osteomyelitis
PubMed: 38108867
DOI: 10.1007/s00393-023-01465-9 -
EMBO Reports Dec 2023Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet...
Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner. Lipin-2 inhibits viral replication both in vitro and in vivo. Moreover, lipin-2 also acts as a regulator of inflammation in a viral context by reducing the signaling through TLR3 and the generation of ROS and release of mtDNA that ultimately activate the NLRP3 inflammasome. Inhibitors of mtDNA release from mitochondria restrict IL-1β production in lipin-2-deficient animals in a model of viral infection. Finally, analyses of databases from COVID-19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease. Overall, these results uncover novel regulatory mechanisms of the IFN response driven by lipin-2 and open new perspectives for the future management of patients with LPIN2 mutations.
Topics: Animals; Humans; DNA, Mitochondrial; Interferons; Phosphatidate Phosphatase
PubMed: 37929625
DOI: 10.15252/embr.202357238 -
Clinical Dysmorphology Jan 2024LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory disease, caused due to biallelic variants in LPIN2 (MIM* 605519). To date, only... (Review)
Review
LPIN2 -related Majeed syndrome (MIM# 609628) is a rare non-inflammasome autoinflammatory disease, caused due to biallelic variants in LPIN2 (MIM* 605519). To date, only 31 individuals from 18 families have been reported with this rare condition. Exome sequencing was done in two affected individuals from two unrelated families. Additionally, phenotypic, and genotypic information from the literature was reviewed. Two novel homozygous missense variants, c.2207G>A p. (Arg736His) and c.1157C>G p. (Ser386Ter) in LPIN2 , were identified in family 1 and family 2 respectively. Chronic recurrent osteomyelitis involving the lower extremities was the most common clinical presentation. LPIN2 -related Majeed syndrome should be considered as a differential diagnosis in an individual with clinical or radiological evidence of recurrent sterile osteomyelitis and chronic anaemia.
Topics: Humans; Osteomyelitis; Immunologic Deficiency Syndromes; Anemia, Dyserythropoietic, Congenital; Syndrome; Nuclear Proteins
PubMed: 37865862
DOI: 10.1097/MCD.0000000000000476 -
Allergy, Asthma, and Clinical... Aug 2023Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms...
BACKGROUND
Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms that were seen at St. Joesph's Healthcare in Hamilton for severe asthma management diagnosed with rare autoinflammatory conditions using genetic molecular analysis.
CASE PRESENTATION
Five patients are included in this case series. Gene mutations associated with familial Mediterranean fever, Yao syndrome, Cryopyrin-associated periodic syndrome, and Majeed syndrome were considered to explain partly the patient's clinical manifestation after comprehensive clinical, biochemical, hematological investigations ruled out other disorders such as parasitosis, Allergic Bronchopulmonary Fungosis, Eosinophilic Granulomatosis with Poly Angitis, IgG4 disease, and Hypereosinophilia syndrome.
CONCLUSIONS
Complex patients initially presenting with respiratory conditions in addition to unexplained autoinflammatory conditions are a diagnostic challenge. Genetic molecular testing provides healthcare practitioners with useful information that may diagnose underlying auto-inflammatory diseases in undifferentiated patients. Role of inflammasome-activation in asthma and eosinophilia needs further investigation.
PubMed: 37644591
DOI: 10.1186/s13223-023-00837-9 -
Frontiers in Pediatrics 2023Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms,... (Review)
Review
Autoinflammatory bone disorders are a group of diseases characterized by sterile osteomyelitis. This includes chronic nonbacterial osteomyelitis and the monogenic forms, Majeed syndrome and deficiency of the interleukin-1 receptor antagonist. These disorders result from innate immune system dysregulation and cytokine imbalance that triggers inflammasome activation causing downstream osteoclastogenesis and excessive bone remodeling. In this review, we will summarize the immunopathogenesis of pediatric autoinflammatory bone diseases with a special focus on the genetics and inborn errors of immunity, while briefly touching on the clinical manifestations and management of each disease as well as areas for future research.
PubMed: 37342528
DOI: 10.3389/fped.2023.1169659 -
Frontiers in Pediatrics 2023Non-bacterial osteomyelitis (NBO) is a rare chronic inflammatory bone disease related to immune system dysregulation. This disease belongs to a family of...
Juvenile idiopathic arthritis with systemic onset with inflammatory bone lesions: two case reports of patients successfully treated with canakinumab and experience gained from literature.
UNLABELLED
Non-bacterial osteomyelitis (NBO) is a rare chronic inflammatory bone disease related to immune system dysregulation. This disease belongs to a family of autoinflammatory diseases. It often coexists with other TNF-α-mediated immune-mediated diseases such as juvenile idiopathic arthritis (JIA) and inflammatory bowel diseases. Previously, interleukin-1-driven inflammation was described predominantly in monogenic cases of NBO, such as DIRA syndrome or Majeed syndrome. However, the association between NBO and JIA with systemic onset (soJIA) has not been described yet. Herein, we describe the cases of two patients with soJIA with inflammatory bone lesions wherein canakinumab (anti-interleukin-1β antibodies) caused remission.
CASE DESCRIPTIONS
Patient 1-A 6-month-old boy with typical soJIA suffered a destruction of the 7th to 9th ribs and the left pubic bone. Antibiotics, IVIG, and cyclosporine proved ineffective. Corticosteroids were effective, but due to the factor of corticosteroid dependence, which has some disadvantages, canakinumab with a dosage of 4 mg/kg was initiated every 4 weeks, which completely controlled the disease and allowed to taper corticosteroids.Patient 2-A 2-year-old girl developed chronic non-bacterial osteomyelitis of the 5th rib 2 months after taking corticosteroids prescribed for typical soJIA. She underwent surgical debridement removal, and several courses of antibiotics proved ineffective. She developed macrophage activation syndrome, following which anakinra was prescribed, which resulted in only temporary improvement. Therefore, this drug was switched to canakinumab, which caused corticosteroid-free remission.
CONCLUSION
This is the first description of a rare association of soJIA with inflammatory bone lesions with the proven efficacy of IL-1 blockade. The association of two autoinflammatory conditions should indicate IL-1-driven mechanisms and a possible genetic basis. Follow-up genetic and functional studies are required to better understand the pathogenesis of such overlapping diseases.
PubMed: 37325364
DOI: 10.3389/fped.2023.1163483 -
Archives of Rheumatology Dec 2022
PubMed: 36879569
DOI: 10.46497/ArchRheumatol.2022.9437 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Dec 2022To summarize the clinical characteristics and provide clues for early identification of non-inflammasome related conditions. The clinical manifestations, laboratory...
To summarize the clinical characteristics and provide clues for early identification of non-inflammasome related conditions. The clinical manifestations, laboratory tests, genetic testing and follow-up of 49 children with non-inflammasome related conditions in Peking Union Medical College Hospital from January 2006 to February 2022 were retrospectively analyzed. A total of 49 children, 29 of them were boys and 20 were girls. The age of onset was 0.8 (0.3, 1.6) years, the age at diagnosis was 5.7 (2.8, 8.8) years, and the time from onset to diagnosis was 3.6 (1.9, 6.3) years. Combined with genetic testing results, 49 children with non-inflammasome related conditions were found, including 34 cases (69%) of Blau syndrome, 4 cases (8%) of tumour necrosis factor receptor-associated periodic syndrome, 4 cases (8%) of haploinsufficiency of A20, 2 cases (4%) of Majeed syndrome, 2 cases (4%) of pyogenic sterile arthritis, pyoderma gangrenosum, acne syndrome and 3 cases (6%) of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. There were 22 cases (45%) with a positive family history. The clinical manifestations included 37 cases (76%) cases with rash, 38 cases (78%) with joint involvement, 33 cases (67%) with eye involvement, 17 cases (35%) with recurrent fever. In addition, 11 cases (22%) were complicated with digestive system involvement. Thirty cases (61%) presented as elevated inflammatory indexes (erythrocyte sedimentation rate and (or) C-reactive protein), positive autoantibodies were noticed in 3 cases (6%). The patients were treated with glucocorticoid in 23 cases (47%), immunosuppressive agents in 43 cases (88%) and biologic agents in 37 cases (76%). During the follow-up of 5.8 (2.9, 8.9) years, 3 cases (6%) died. The symptoms of non-inflammasome related conditions include recurrent fever, rash, joint and ocular involvement with increased inflammatory indexes and negative autoantibodies. Up to now, glucocorticoids, immunosuppressants and biologic agents are the most popular medications for the non-inflammasome related conditions.
Topics: Male; Child; Female; Humans; Retrospective Studies; Synovitis; Arthritis, Infectious; Exanthema; Glucocorticoids; Autoantibodies
PubMed: 36444428
DOI: 10.3760/cma.j.cn112140-20220620-00570 -
Pediatric Rheumatology Online Journal Oct 2022Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease... (Review)
Review
BACKGROUND
Systemic autoinflammatory diseases (SAIDs) are hyperinflammatory and immune-dysregulation conditions that present in childhood. This kind of disease is a rare disease with early-onset, severe condition and difficult diagnosis, which seriously affects the growth and development of children. Most children need a genetic diagnosis. However, with the limitation of access to genetic testing and the detection of somatic mutations, the diagnosis of SAIDs remains challenging. IL-1 is one of the important cytokines involved in the pathogenesis of SAIDs. Here we briefly review monogenic SAIDs mediated by aberrant IL-1 production, with the aim to further understand the pathogenesis, clinical manifestations and treatments of IL-1 mediated SAIDs.
METHODS
Literature reviews were performed using "PubMed" and "Web of Science" by searching for the terms "autoinflammatory diseases" and "IL-1".
RESULTS
Monogenic SAIDs mediated by IL-1 include MKD, FMF, TRAPS, PAAND, PAPA, CAPS, DIRA, Majeed syndrome, NAIAD, NLRC4-MAS, PFIT, APLAID. Monogenic SAIDs have early onset, various clinical manifestations and difficult diagnosis, so early recognition and early treatment can reduce the complications and enhance the quality of life.
CONCLUSIONS
There are many kinds of IL-1 mediated SAIDs. Pediatricians should be alert to SAIDs in the face of the patients with repeated fever, repeated rash and poor effect of routine treatment. The patients should be carried out with gene testing and treatment in time.
Topics: Animals; Child; Cytokines; Genetic Testing; Hereditary Autoinflammatory Diseases; Humans; Quality of Life; Simian Acquired Immunodeficiency Syndrome
PubMed: 36253853
DOI: 10.1186/s12969-022-00728-0